It is clear that alcohol abuse can alter/suppress immune function, including CD4 T-lymphocyte depletion, which can accelerate HIV progression. Subjects who consume alcohol may be more likely to develop certain infectious diseases which can complicate HIV, examples being various types of pneumonia and tuberculosis. Moreover, subjects who consume alcohol are more likely to participate in high-risk behaviors that increase the likelihood of acquiring HIV. Patients who consume alcohol also may be less compliant with their HIV therapy, which can affect disease progression. The research focus of this grant is the potential impact of alcohol use/abuse as a co-factor for HIV therapy-induced hepatotoxicity. Since the introduction of highly active antiretroviral therapy (HAART) in 1996, the life expectancy of patients with HIV has increased significantly. However, HAART is associated with significant hepatotoxicity. The severity of liver toxicity ranges from the absence of symptoms to liver decompensation, and the reported incidence of severe liver toxicity after initiating HAART ranges from 2% to 18%. The mechanisms involved in HAART-derived hepatotoxicity are not well understood, which makes its management more difficult. Some likely mechanisms of hepatotoxicity include proinflammatory cytokine production mitochondrial toxicity, hypersensitivity reactions, steatosis and insulin resistance, immune reconstitution in HCV or HBV co-infected patients, and proteasome inhibition (with dysregulated cytokine metabolism and mitochondrial and proteasome dysfunction serving as the focus of this proposal). The long-term goals of this study are to: (1) define mechanisms of hepatotoxicity induced by a combination of drug therapy and alcohol abuse in HIV patients and (2) discover potential therapeutic interventions for HAART hepatotoxicity, especially for patients in whom alcohol use/abuse may be a contributing factor. Specific Aims of this proposal are to: 1. Evaluate the potential hepatotoxic interactions of alcohol and HAART medications using rapid in vitro hepatocyte screening technology; 2. Determine the effects of anti- HIV drugs (selected agents based on preliminary toxicity studies from SO#1 and clinical hepatotoxicity risk), on the development and progression of hepatotoxicity in mice and the drug interactions with chronic alcohol intake; and 3. Evaluate in a human translational component: a) mitochondrial and proteasome function and ex vivo cytokine production in subsets of HIV patients, b) serial non-invasive measures of mitochondrial and proteasome function and cytokine production in patients who develop HAART hepatotoxicity, and c) liver histology findings including markers of proteasome and mitochondrial function, using a human translational approach from a cohort of HCV+HIV coinfected subjects enrolled in a prospective NIH study based at the University of Cincinnati. We postulate that the HAART and alcohol mediated metabolic complications of dysregulated proinflammatory cytokine production and mitochondrial and proteasome dysfunction converge on the liver in an overlapping fashion to induce hepatotoxicity. In this proposal, we test that hypothesis in a novel translational approach and we evaluate unique therapeutic interventions for this hepatotoxicity. PUBLIC HEALTH RELEVANCE: Alcohol abuse and HIV are important health problems. Liver disease is recognized as an increasingly important problem for the HIV population. Liver disease may be due to a variety of factors including co-infection with viral hepatitis, alcohol abuse, and antiretroviral hepatotoxicity. Liver disease is now a leading cause of death for patients with HIV. Hepatotoxicity due to HAART is also common, and up to 30% of patients on HAART experience World Health Organization grade 3 liver enzyme elevations. Furthermore, hepatotoxicity from antiretroviral drugs leads to adverse patient outcomes either from fulminant hepatic failure, or more commonly, AIDS following discontinuation of HAART. It is unknown why some, but not all HIV patients develop drug induced liver injury from HAART. Relevant to this proposal, alcohol/HAART interactions are emerging as critically important factors. Recent research has shown that alcohol abuse is associated with severe hepatotoxicity in patients on HAART. Importantly, alcoholic liver disease and HAART induced liver injury share many potential mechanisms of injury. These include cytokine dysregulation, mitochondrial dysfunction, and proteasomal dysfunction. Through these and other mechanisms, alcohol and antiretroviral medications converge on the liver in an overlapping fashion to produce hepatotoxicity. Here, we will study hepatotoxicity due to alcohol/HAART interactions to further define disease mechanisms and create therapeutic interventions.